Anti-cancer therapy is associated with long-term epigenomic changes in childhood cancer survivors.
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
07 2022
07 2022
Historique:
received:
19
08
2021
accepted:
11
03
2022
revised:
24
02
2022
pubmed:
1
4
2022
medline:
22
7
2022
entrez:
31
3
2022
Statut:
ppublish
Résumé
Childhood cancer survivors (CCS) exhibit significantly increased chronic diseases and premature death. Abnormalities in DNA methylation are associated with development of chronic diseases and reduced life expectancy. We investigated the hypothesis that anti-cancer treatments are associated with long-term DNA methylation changes that could be key drivers of adverse late health effects. Genome-wide DNA methylation was assessed using MethylationEPIC arrays in paired samples (before/after therapy) from 32 childhood cancer patients. Separately, methylation was determined in 32 samples from different adult CCS (mean 22-years post-diagnosis) and compared with cancer-free controls (n = 284). Widespread DNA methylation changes were identified post-treatment in childhood cancer patients, including 146 differentially methylated regions (DMRs), which were consistently altered in the 32 post-treatment samples. Analysis of adult CCS identified matching methylation changes at 107/146 of the DMRs, suggesting potential long-term retention of post-therapy changes. Adult survivors also exhibited epigenetic age acceleration, independent of DMR methylation. Furthermore, altered methylation at the DUSP6 DMR was significantly associated with early mortality, suggesting altered methylation may be prognostic for some late adverse health effects in CCS. These novel methylation changes could serve as biomarkers for assessing normal cell toxicity in ongoing treatments and predicting long-term health outcomes in CCS.
Sections du résumé
BACKGROUND
Childhood cancer survivors (CCS) exhibit significantly increased chronic diseases and premature death. Abnormalities in DNA methylation are associated with development of chronic diseases and reduced life expectancy. We investigated the hypothesis that anti-cancer treatments are associated with long-term DNA methylation changes that could be key drivers of adverse late health effects.
METHODS
Genome-wide DNA methylation was assessed using MethylationEPIC arrays in paired samples (before/after therapy) from 32 childhood cancer patients. Separately, methylation was determined in 32 samples from different adult CCS (mean 22-years post-diagnosis) and compared with cancer-free controls (n = 284).
RESULTS
Widespread DNA methylation changes were identified post-treatment in childhood cancer patients, including 146 differentially methylated regions (DMRs), which were consistently altered in the 32 post-treatment samples. Analysis of adult CCS identified matching methylation changes at 107/146 of the DMRs, suggesting potential long-term retention of post-therapy changes. Adult survivors also exhibited epigenetic age acceleration, independent of DMR methylation. Furthermore, altered methylation at the DUSP6 DMR was significantly associated with early mortality, suggesting altered methylation may be prognostic for some late adverse health effects in CCS.
CONCLUSIONS
These novel methylation changes could serve as biomarkers for assessing normal cell toxicity in ongoing treatments and predicting long-term health outcomes in CCS.
Identifiants
pubmed: 35354948
doi: 10.1038/s41416-022-01792-9
pii: 10.1038/s41416-022-01792-9
pmc: PMC9296636
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
288-300Subventions
Organisme : Medical Research Council
ID : MR/S019669/1
Pays : United Kingdom
Informations de copyright
© 2022. The Author(s).
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